Mitochondrial deficiency impairs hypoxic induction of HIF-1 transcriptional activity and retards tumor growth
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE80320 | GEO | 2017/01/01
SECONDARY ACCESSION(S): PRJNA318582
REPOSITORIES: GEO
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Project description:DNA Topoisomerase I inhibition by Camptothecin (CPT) derivatives can impair the hypoxia-induced cell transcriptional response. In the present work, we determined molecular aspects of the mechanism of CPT effects on HIF-1alpha activity in human cancer cells. In particular, we provide evidence that low concentrations of CPT, without interfering with HIF-1alpha mRNA levels, can reduce HIF-1alpha protein expression and activity. As luciferase assays demonstrated the involvement of the HIF-1alpha mRNA 3M-^RUTR in CPT-induced impairment of HIF-1alpha protein regulation, we performed microarray analysis to identify CPT-induced modification of miRNAs targeting HIF-1alpha mRNA under hypoxic-mimetic conditions. The selected miRNAs were then further analyzed demonstrating a role for miR-17-5p and miR-155 in HIF-1alpha protein expression after CPT treatments. The present findings establish miRNAs as key factors in a molecular pathway connecting Top1 inhibition and human HIF-1alpha protein regulation and activity, widening the biological and molecular activity of CPT derivatives and the perspective for novel clinical interventions.
2013-12-02 | E-MTAB-2022 | biostudies-arrayexpress
Project description:Intestinal epithelia exist in a uniquely dynamic oxygen tension microenvironment. Adaptive responses to hypoxia in mammalian cells are regulated largely by hypoxia inducible factor (HIF) transcriptional complexes. Functional HIF exists as an obligate alpha/beta heterodimer, comprising both a constitutive subunit (HIF-1beta), and an oxygen-labile regulatory (alpha) component. To date, three regulatory subunits have been identified, namely HIF-1alpha, HIF-2alpha, and HIF-3alpha, with the highest level of sequence homology conserved between HIF-1alpha and HIF-2alpha. Despite their concurrent expression in intestinal epithelial cells, HIF-1 and HIF-2 play non-redundant roles in the regulation of an overlapping but distinct set of gene targets. In this study, we performed ChIP-on-chip analysis of chromatin isolated from hypoxic intestinal epithelia to delineate HIF-1 and HIF-2 specific loci. Comparison of HIF-1alpha ChIP-chip and HIF-2alpha ChIP-chip to map HIF-1- and HIF-2-specific gene targets across the genome.
2013-11-05 | E-GEOD-43108 | biostudies-arrayexpress
Project description:Comprehensive analysis of coding and non -coding transcriptome using ribo-depleted total RNA-seq and poly A selected RNA-seq of MCF-7 cells grown in hypoxia and normoxia. Breast cancer cell line (MCF-7) is cultured in normoxic condition (21% O2) and hypoxic condition (1%O2) for 24 hours. Expression of HIF-1alpha and/or HIF-2alpha subunits was suppressed using siRNAs in hypoxic MCF-7 cells. Total RNA was isolated from both hypoxia and normoxia conditions were subjected for ribosomal depleted stand specific RNA-seq and poly A selected RNA-seq
2014-02-10 | E-MTAB-1994 | biostudies-arrayexpress
Project description:The activation of the transcription factor Hypoxia-inducible factor-1 (HIF-1) plays an essential role in tumor development, tumor progression and resistance to chemo- and radiotherapy. In order to identify compounds targeting the HIF pathway, a small-molecule library was screened using a luciferase-driven HIF-1 reporter cell line under hypoxia. The high throughput screen led to the identification of a class of aminoalkyl-substituted compounds that inhibited hypoxia-induced HIF-1 target gene expression in human lung cancer cell lines at low nanomolar concentrations but did not affect expression levels of genes outside of the HIF-1 pathway. Lead structure BAY 87-2243 was found to inhibit HIF-1α protein accumulation under hypoxic conditions in NSCLC cell line H460 but had no effect on HIF-1α protein accumulation and HIF target gene expression in RCC4 cells lacking VHL activity or in H460 cells after inhibition of HIF prolyl hydroxylase activity. BAY 87-2243 had no effect on HIF-α-mRNA levels. Antitumor activity of BAY 87-2243 and suppression of HIF-1 target gene expression in vivo was demonstrated in a H460 xenograft model. BAY 87-2243 did not inhibit cell proliferation under standard conditions. However under glucose depletion, a condition favoring mitochondrial ATP generation as energy source, BAY 87-2243 inhibited cell proliferation in the nanomolar range. Further experiments revealed that BAY 87-2243 inhibits mitochondrial production of reactive oxygen species (ROS) by blocking complex I activity but has no effect on complex III activity. Lowering of mitochondrial ROS production to reduce hypoxia-induced HIF-1 activity in tumors might be an interesting therapeutic approach to overcome chemo- and radiotherapy-resistance of hypoxic tumors. We used microarrays to detail the global programme of gene expression that is induced in NSCLC cell line H460 upon hypoxia (16 h incubation at 1 % pO2) and evaluated a dose-dependent effect of our HIF-1-pathway inhibitor BAY 87-2243 on genes tthat are affected by hypoxia. Specificity of BAY 87-2243 for the suppression of HIF-1-mediated gene transcription on a genome-wide scale was evaluated by microarray hybridizations using Affymetrix GeneChip Human Gene 1.0 ST arrays. RNA from normoxic H460 cells and from hypoxic H460 cells incubated with 1, 10 and 100 nM BAY 87-2243 respectively was subjected to array hybridization. Of those 30 genes that were most strongly suppressed by 100 nM BAY 87-2243 in hypoxic H460 cells compared to DMSO-treated hypoxic H460 cells, virtually all of them are induced by prior hypoxia and most of these genes have been described in the literature as HIF-1 target genes
2012-12-08 | E-GEOD-42791 | biostudies-arrayexpress
Project description:Intestinal epithelia exist in a uniquely dynamic oxygen tension microenvironment. Adaptive responses to hypoxia in mammalian cells are regulated largely by hypoxia inducible factor (HIF) transcriptional complexes. Functional HIF exists as an obligate alpha/beta heterodimer, comprising both a constitutive subunit (HIF-1beta), and an oxygen-labile regulatory (alpha) component. To date, three regulatory subunits have been identified, namely HIF-1alpha, HIF-2alpha, and HIF-3alpha, with the highest level of sequence homology conserved between HIF-1alpha and HIF-2alpha. Despite their concurrent expression in intestinal epithelial cells, HIF-1 and HIF-2 play non-redundant roles in the regulation of an overlapping but distinct set of gene targets. In this study, we performed ChIP-on-chip analysis of chromatin isolated from hypoxic intestinal epithelia to delineate HIF-1 and HIF-2 specific loci.
2013-11-05 | GSE43108 | GEO
Project description:Hypoxia is closely linked to chemotherapy resistance and accelerates breast cancer progression. However, the underlying mechanism of resistance to hypoxic chemotherapy remains uncertain. ZNF207 was identified as a differentially expressed gene involved in hypoxia and chemotherapy resistance by RNA-sequencing array. ZNF207 expression was elevated in lung, breast, liver, colon, and ovarian cancers, and its positive expression was correlated significantly with advanced TNM stage, lymph node metastasis, and poor prognosis. ZNF207 overexpression promoted the proliferation, invasion capabilities, and stemness of breast cancer cells by activating the HIF-1alpha-PPAR-gamma-glycolysis signaling pathway. Notably, ZNF207 was directly bound to the coiled-coil domain of YWHAZ, thereby accelerating HIF-1alpha deacetylation in an HDAC4-dependent manner. Furthermore, ZNF207 might stabilize YWHAZ by inhibiting its degradation via TRIM67 through a ubiquitin-dependent mechanism. ZNF207 overexpression enhanced resistance to doxorubicin and vinorelbine. Conversely, ZNF207-DeltaGLE overexpression disrupted HIF-1alpha-PPAR-gamma-glycolysis signaling and abolished chemotherapy resistance. Additionally, ZNF207 expression was higher in patients with breast cancer who exhibited poor treatment outcomes (Miller/Payne grades 1-2) than in those with more favorable outcomes (Miller/Payne grades 3-5). Sappanchalcone, a specific ZNF207 inhibitor, impedes breast cancer progression while exerting a synergistic effect with chemotherapy. Our findings revealed that ZNF207 expression was elevated in breast cancer under hypoxic conditions, promoting proliferation and invasion by activating HIF-1alpha through accelerated deacetylation in a positive feedback loop. The interaction between ZNF207 and YWHAZ enhances HIF-1alpha stability, ultimately accelerating therapeutic resistance in breast cancer.
2024-10-16 | GSE279294 | GEO
Project description:Hypoxia is closely linked to chemotherapy resistance and accelerates breast cancer progression. However, the underlying mechanism of resistance to hypoxic chemotherapy remains uncertain. ZNF207 was identified as a differentially expressed gene involved in hypoxia and chemotherapy resistance by RNA-sequencing array. ZNF207 expression was elevated in lung, breast, liver, colon, and ovarian cancers, and its positive expression was correlated significantly with advanced TNM stage, lymph node metastasis, and poor prognosis. ZNF207 overexpression promoted the proliferation, invasion capabilities, and stemness of breast cancer cells by activating the HIF-1alpha-PPAR-gamma-glycolysis signaling pathway. Notably, ZNF207 was directly bound to the coiled-coil domain of YWHAZ, thereby accelerating HIF-1alpha deacetylation in an HDAC4-dependent manner. Furthermore, ZNF207 might stabilize YWHAZ by inhibiting its degradation via TRIM67 through a ubiquitin-dependent mechanism. ZNF207 overexpression enhanced resistance to doxorubicin and vinorelbine. Conversely, ZNF207-DeltaGLE overexpression disrupted HIF-1alpha-PPAR-gamma-glycolysis signaling and abolished chemotherapy resistance. Additionally, ZNF207 expression was higher in patients with breast cancer who exhibited poor treatment outcomes (Miller/Payne grades 1-2) than in those with more favorable outcomes (Miller/Payne grades 3-5). Sappanchalcone, a specific ZNF207 inhibitor, impedes breast cancer progression while exerting a synergistic effect with chemotherapy. Our findings revealed that ZNF207 expression was elevated in breast cancer under hypoxic conditions, promoting proliferation and invasion by activating HIF-1alpha through accelerated deacetylation in a positive feedback loop. The interaction between ZNF207 and YWHAZ enhances HIF-1alpha stability, ultimately accelerating therapeutic resistance in breast cancer.
2024-10-21 | GSE279443 | GEO
Project description:Hypoxia and inflammation are key factors for colorectal cancer tumorigenesis. The colonic epithelium belongs to the tissues with the lowest partial pressure of oxygen in the body, and chronic inflammation is associated with an increased chance to develop colon cancer. How the colonic epithelium responds to hypoxia and inflammation during tumorigenesis remains to be elucidated. Here we show, that murine colon adenocarcinoma cells with attenuated response to hypoxia, due to a knock-down (KD) of HIF-1alpha produce smaller and less hypoxic tumors in an orthotopic mouse model when compared to tumors induced with control cells. HIF-1alpha-KD tumors showed more functional perfused vasculature associated with increased levels of vessel-stabilizing factors and reduced levels of pro-angiogenic factors, including extracellular matrix protein Cyr61/CCN1. Intratumoral injection of Cyr61 in HIF-1alpha-KD tumors revealed an in increased vessel permeability and tumor hypoxia. Further bioinformatics analysis identified a possible interaction between HIF-1alpha and TRAF6, an upstream effector of the NF-kappaB pathway that was confirmed by co-immunoprecipitation in MC-38 and CT26 colon adenocarcinoma cells. Down-regulation of TRAF6 resulted in virtual abrogation of orthotopic tumor growth. Subcutaneous TRAF6-KD tumors were smaller and contained reduced vessel size and differently polarized macrophages. These data demonstrate that the tumor cell response to increased hypoxia in the colon leads to promotion of non-functional angiogenesis, regulated by both hypoxia and TRAF6 pathways.
2020-11-09 | GSE155104 | GEO
Project description:Investigation whether hypoxic stabilization of HIF-1alpha quantitatively or qualitatively modifies the gene expression pattern induced by poly I:C, a TLR ligand that does not induce normoxic HIF-1alpha stabilization on its own (non-HIF-1alpha-stabilizing TLR ligand). Keywords: Comparison of single and combined treatment
2011-06-29 | GSE24995 | GEO
Project description:The response of cells to hypoxia is characterised by co-ordinated regulation of many genes. Studies of the regulation of the expression of many of these genes by oxygen has implicated a role for the heterodimeric transcription factor hypoxia inducible factor (HIF). The mechanism of oxygen sensing which controls this heterodimeric factor is via oxygen dependent prolyl and asparaginyl hydroxylation by specific 2-oxoglutarate dependent dioxygenases (PHD1, PHD2, PHD3 and FIH-1). Whilst HIF appears to have a major role in hypoxic regulation of gene expression, it is unclear to what extent other transcriptional mechanisms are also involved in the response to hypoxia. The extent to which 2-oxoglutarate dependent dioxygenases are responsible for the oxygen sensing mechanism in HIF-independent hypoxic gene regulation is also unclear. Both the prolyl and asparaginyl hydroxylases can be inhibited by dimethyloxalylglycine (DMOG). Such inhibition can produce activation of the HIF system with enhanced transcription of target genes and might have a role in the therapy of ischaemic disease. We have examined the extent to which the HIF system contributes to the regulation of gene expression by hypoxia, to what extent 2-oxoglutarate dependent dioxygenase inhibitor can mimic the hypoxic response and the nature of the global transcriptional response to hypoxia. We have utilised microarray assays of mRNA abundance to examine the gene expression changes in response to hypoxia and to DMOG. We demonstrate a large number of hypoxically regulated genes, both known and novel, and find a surprisingly high level of mimicry of the hypoxic response by use of the 2-oxoglutarate dependent dioxygenase inhibitor, dimethyloxalylglycine. We have also used microarray analysis of cells treated with small interfering RNA (siRNA) targeting HIF-1alpha and HIF-2alpha to demonstrate the differing contributions of each transcription factor to the transcriptional response to hypoxia. Candidate transcripts were confirmed using an independent microarray platform and real-time PCR. The results emphasise the critical role of the HIF system in the hypoxic response, whilst indicating the dominance of HIF-1alpha and defining genes that only respond to HIF-2alpha. Keywords: Hypoxia response, gene knockdown, chemical treatment
2005-12-01 | GSE3188 | GEO